The microorganisms that have developed resistance to available therapeutic agents are threatening the globe and multidrug resistance among the bacterial pathogens is becoming a major concern of public health worldwide. Bacteria develop protective mechanisms to counteract the deleterious effects of antibiotics, which may eventually result in loss of growth-inhibitory potential of antibiotics. ESKAPE ( and spp.) pathogens display multidrug resistance and virulence through various mechanisms and it is the need of the hour to discover or design new antibiotics against ESKAPE pathogens. In this article, we have discussed the mechanisms acquired by ESKAPE pathogens to counteract the effect of antibiotics and elaborated on recently discovered secondary metabolites derived from bacteria and plant sources that are endowed with good antibacterial activity towards pathogenic bacteria in general, ESKAPE organisms in particular. Abyssomicin C, allicin, anthracimycin, berberine, biochanin A, caffeic acid, daptomycin, kibdelomycin, piperine, platensimycin, plazomicin, taxifolin, teixobactin, and thymol are the major metabolites whose antibacterial potential have been discussed in this article.